Hyperphosphatemia in patients with chronic renal failure is a serious problem which may lead to osteoitis fibrosa or calcium phosphate deposition in soft tissue. Various approaches have been used to lower serum phosphate. Aluminum hydroxide in an oral dosage form has been used to bind dietary phosphate. However, aluminum accumulates in patients with renal failure and its accumulation has been associated with dysfunction of various organ systems. Aluminum-associated osteomalacia has been shown to occur in patients whose only substantial exposure to aluminum was their intake of aluminum-containing phosphate binders.
Calcium carbonate therapy is another method which has been used for serum phosphate control. Serum calcium levels are known to increase significantly after treatment with calcium carbonate, in spite of decreased mean calcitriol dosage and suppression of parathyroid activity. This increase in serum calcium is thought to be attributed to increased gastrointestinal absorption of calcium that is not vitamin D dependent. Calcification of soft tissues and the vasculature are a potential risk associated with elevated calcium/phosphate ion product. Metastatic calcifications of the eyes, joints, viscera, skin and arteries can occur as calcium phosphate salts precipitate as a direct consequence of supersaturation of body fluids with calcium phosphates. Hyperphosphatemia has been seen as the most important factor in the mechanism of soft-tissue calcification in uremia. Additionally, calcium carbonate is not suitable for use in chronic renal failure patients who are hypercalcemic. Gastrointestinal distress may be manifested in some patients taking calcium carbonate. A recent letter in the New England Journal of Medicine [Stein et al., Vol. 316, p. 109 (1987)] reported high serum values and pancolonic impaction in patients with end-stage renal disease in which calcium carbonate was substituted for aluminum binders. The writers there cautioned against overzealous use of calcium carbonate as a phosphate binder.
Magnesium-containing phosphate binders have been used for treatment of hyperphosphatemia. However, such binders have been associated with hypermagnesemia, even with the use of a low magnesium dialysate. Other products advocated for use as phosphate binders such as calcium and iron cation loaded polyuronic acids require dosages of 5-10 grams per day.
There is recognized in the medical community a significant need for the development of a phosphate binder which ideally should be palatable, free of even minor side effects, inexpensive and very efficient in binding phosphate under physiological conditions. Accordingly, it is one object of this invention to provide a method for controlling serum phosphate utilizing a phosphate binding oxy-iron compound.
It is another object of this invention to provide a composition in an oral dosage form for inhibiting the absorption of dietary phosphate.
It is still another object of this invention to provide a composition which not only has been identified as an efficient phosphate binder, but has the added advantage of being insoluble or but slightly soluble in physiological fluids.
Another object of this invention is to provide a method for enhancing reduction of a patient's serum phosphate levels during hemodialysis by contacting a phosphate binding oxy-iron compound with the dialysate.
In accordance with this invention oxy-iron compounds, including particularly iron oxides and iron oxyhydroxides, have been determined to be effective agents for preventing absorption of ingested phosphates in the digestive tract. Not only do such compositions exhibit a high adsorptive capacity for phosphate, but they also exhibit low solubility in physiological fluids, including gastric juices, thereby lessening the probability of side effects due to absorption of solubilized iron compounds. Oxy-iron compounds can be utilized in accordance with this invention in an oral dosage form to bind and thereby prevent absorption of ingested phosphate from the intestine and, alternatively, can be used as an additive in dialysate used for hemodialysis to effect and maintain a low phosphate concentration in the dialysate and thereby promote reduction of a patient's serum phosphate level during hemodialysis.
Synthetic ferrihydrite (Fe.sub.5 O.sub.7 (OH).sup.. 4H.sub.2 O), a preferred oxy-iron compound for use in accordance with the present invention has been found to exhibit a high adsorptive capacity for phosphate, 32 mg P/g and was virtually insoluble in simulated gastric acid. It is projected that a 174 mg dose of ferrihydrite can adsorb the same amount of phosphate as 10 ml of the art-recognized aluminum hydroxide phosphate binder.